The general objective of this research project is to study the effect of hyperthermia alone or combined with radiation on murine tumor and normal tissues. Specific aims are; to study the effect of artificial acidosis on the kinetics of thermal resistance, the size of hypoxic cell fraction and the frequency of metastases, to investigate late damages and carcinogenesis following combined hyperthermia and radiotherapy, and to study thermal response and thermal resistance in various normal tissues. Animals will be C3Hf/Sed mice derived from our defined flora colony. FSa-II (fibrosarcoma) and MCa (mammary carcinoma), which arose spontaneously, and a chemically-induced fibrosarcoma FSa-I will be used. In vivo assay methods are to be employed. It is well documented that tumors contain foci of oxygen deficient but clonogenic cells. These hypoxic and hence radioresistant cells have been considered to be critical for radiotherapy. A rationale of using hyperthermia is that hypoxic tumor cells are as sensitive as well-oxygenated cells to heat treatment. There is increasing evidence that a decrease in environmental pH is associated with increasing thermal sensitivity, and tumor tissue pH is lower than normal tissue pH. This project will attempt to enhance thermal sensitivity of tumor tissues by inducing acidosis and will study the effect of the acidosis on various factors involved in hyperthermia given alone or combined with radiation, as mentioned above. Recent studies demonstrated a weak carcinogenic effect of hyperthermia, providing a strong rationale for use of hyperthermia in cancer treatment. This project will investigate late damage and carcinogenesis following combined heat and radiation therapy (high incidence of secondary neoplasms are demonstrated following radiation). In addition, thermal response of normal tissues consisting of non-proliferating or slowly proliferating cells will be studied since post-treatment cell kinetics is apparently different from that following radiation. Pursuit of these objectives will establish a solid biological basis for effective use of hyperthermia in human cancer treatment.